title: P2X7 purinoceptors contribute to the death of Schwann cells transplanted into the spinal cord.
abstract: The potential to use Schwann cells (SCs) in neural repair for patients suffering from neurotrauma and neurodegenerative diseases is well recognized. However, significant cell death after transplantation hinders the clinical translation of SC-based therapies. Various factors may contribute to the death of transplanted cells. It is known that prolonged activation of P2X7 purinoceptors (P2X7R) can lead to death of certain types of cells. In this study, we show that rat SCs express P2X7R and exposure of cultured SCs to high concentrations of ATP (3-5 mM) or a P2X7R agonist, 2'(3')-O-(4-benzoylbenzoyl)ATP (BzATP) induced significant cell death rapidly. High concentrations of ATP and BzATP increased ethidium uptake by SCs, indicating increased membrane permeability to large molecules, a typical feature of prolonged P2X7R activation. SC death, as well as ethidium uptake, induced by ATP was blocked by an irreversible P2X7R antagonist oxidized ATP (oxATP) or a reversible P2X7R antagonist A438079. oxATP also significantly inhibits the increase of intracellular free calcium induced by minimolar ATP concentrations. Furthermore, ATP did not cause death of SCs isolated from P2X7R-knockout mice. All these results suggest that P2X7R is responsible for ATP-induced SC death in vitro. When rat SCs were treated with oxATP before transplantation into uninjured rat spinal cord, 35% more SCs survived than untreated SCs 1 week after transplantation. Moreover, 58% more SCs isolated from P2X7R-knockout mice survived after being transplanted into rat spinal cord than SCs from wild-type mice. This further confirms that P2X7R is involved in the death of transplanted SCs. These results indicate that targeting P2X7R on SCs could be a potential strategy to improve the survival of transplanted cells. As many other types of cells, including neural stem cells, also express P2X7R, deactivating P2X7R may improve the survival of other types of transplanted cells.
authors.affiliation: 1] Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, London E1 2AT, UK [2] Department of Physiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: J
authors.initials: J
authors.lastname: Luo
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.forename: D
authors.initials: D
authors.lastname: Wu
authors.forename: J
authors.initials: J
authors.lastname: Yeh
authors.forename: H
authors.initials: H
authors.lastname: Ellamushi
authors.forename: A P
authors.initials: AP
authors.lastname: Wheeler
authors.forename: G
authors.initials: G
authors.lastname: Warnes
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: X
authors.initials: X
authors.lastname: Bo
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004705:Endocytosis / Q000187:drug effects; D004996:Ethidium / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation*; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology*; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: C523668:3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine; D058920:Purinergic P2X Receptor Antagonists; D011725:Pyridines; D058486:Receptors, Purinergic P2X7; D013777:Tetrazoles; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; C017199:2',3'-dialdehyde ATP; D000255:Adenosine Triphosphate; D004996:Ethidium; D002118:Calcium